Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear. METHODS: In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response. RESULTS: A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups. CONCLUSIONS: Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.).

Inhaled Technosphere Insulin Compared With Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24-Week Trial.

OBJECTIVE: To compare the efficacy and safety of Technosphere insulin (TI) and insulin aspart in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: This open-label noninferiority trial compared the change in HbA1c from baseline to week 24 of prandial TI (n = 174) with that of subcutaneous aspart (n = 171), both with basal insulin, in patients with type 1 diabetes and HbA1c 7.5-10.0% (56.8-86.0 mmol/mol). RESULTS: Mean change in HbA1c in TI patients (-0.21% [-2.3 mmol/mol]) from baseline (7.94% [63.3 mmol/mol]) was noninferior to that in aspart patients (-0.40% [-4.4 mmol/mol]) from baseline (7.92% [63.1 mmol/mol]). The between-group difference was 0.19% (2.1 mmol/mol) (95% CI 0.02-0.36), satisfying the noninferiority margin of 0.4%. However, more aspart patients achieved HbA1c <7.0% (53.0 mmol/mol) (30.7% vs. 18.3%). TI patients had a small weight loss (-0.4 kg) compared with a gain (+0.9 kg) for aspart patients (P = 0.0102). TI patients had a lower hypoglycemia event rate than aspart patients (9.8 vs. 14.0 events/patient-month, P < 0.0001). Cough (generally mild) was the most frequent adverse event (31.6% with TI, 2.3% with aspart), leading to discontinuation in 5.7% of patients. Treatment group difference for mean change from baseline in forced expiratory volume in 1 s was small (40 mL) and disappeared upon TI discontinuation. CONCLUSIONS: In patients with type 1 diabetes receiving basal insulin, HbA1c reduction with TI was noninferior to that of aspart, with less hypoglycemia and less weight gain but increased incidence of cough.

Experience with intravenous ferric carboxymaltose in patients with iron deficiency anemia.

Erythropoiesis may be limited by absolute or functional iron deficiency or when chronic inflammatory conditions lead to iron sequestration. Intravenous iron may be indicated when oral iron cannot address the deficiency. Ferric carboxymaltose (FCM) is a nondextran iron preparation recently approved in the United States for intravenous treatment of iron deficiency anemia (IDA) in adult patients with intolerance or unsatisfactory response to oral iron or with nondialysis-dependent chronic kidney disease. The full dose is two administrations of up to 750 mg separated by at least 7 days (up to 1500 mg total). FCM can be injected in 7-8 min or diluted in saline for slower infusion. The efficacy and safety of this dose was established in two prospective trials that randomized over 3500 subjects, 1775 of whom received FCM. One trial showed similar efficacy of FCM to an approved intravenous iron regimen (1000 mg of iron sucrose) in 2500 subjects with chronic kidney disease and additional cardiovascular risk factors. The other trial showed superior efficacy of FCM to oral iron in subjects with IDA due to various etiologies (e.g. gastrointestinal or uterine bleeding). In these trials, there was no significant difference between FCM and comparator with respect to an independently adjudicated composite safety endpoint, including death, myocardial infarction, or stroke. A database of 5799 subjects exposed to FCM provided a safety profile acceptable for regulatory approval. Mechanistic studies demonstrated that the transient, asymptomatic reduction in serum phosphate observed following FCM administration results from induction of fibroblast growth factor 23, which in turn induces renal phosphate excretion. An elevated hepcidin level may identify patients with IDA who will not respond to oral iron but will respond to FCM. The ability to administer FCM in two rapid injections or infusions will likely be viewed favorably by patients and healthcare providers.

Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial.

BACKGROUND: Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD. METHODS: A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events. RESULTS: The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group. CONCLUSIONS: Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.

A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia.

BACKGROUND: Many patients receiving oral iron for iron deficiency anemia (IDA) cannot tolerate or fail to respond to therapy, and existing intravenous (IV) iron formulations often require repeated administrations. Ferric carboxymaltose (FCM), a nondextran IV formulation, permits larger single doses. STUDY DESIGN AND METHODS: We evaluated FCM versus oral iron in IDA patients. After 14 days of oral iron, 507 participants responding inadequately to oral iron (hemoglobin [Hb] increase <1 g/dL; Cohort 1) were assigned to Group A (two doses of FCM, 750 mg, 1 week apart) or Group B (oral iron, 325 mg, 3 × day for 14 additional days). Also, 504 subjects not appropriate for oral iron (Cohort 2) were assigned to Group C (FCM as above) or Group D (standard-of-care IV iron). The primary efficacy endpoint was change to highest observed Hb from baseline to Day 35. The composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, arrhythmias, and hyper- or hypotensive events. RESULTS: Mean (± standard deviation [SD]) Hb increase was significantly greater in Group A-FCM than Group B-oral iron: 1.57 (±1.19) g/dL versus 0.80 (±0.80) g/dL (p = 0.001). Post hoc comparison of Group C-FCM and Group D-IV standard of care also demonstrated significant mean (±SD) increase in Hb from baseline to highest value by Day 35 in Group C versus Group D: 2.90 (±1.64) g/dL versus 2.16 (±1.25) g/dL (p = 0.001). Safety endpoints occurred in 17 of 499 (3.4%) participants receiving FCM versus 16 of 498 (3.2%) in comparator groups. CONCLUSION: Two 750-mg FCM infusions are safe and superior to oral iron in increasing Hb levels in IDA patients with inadequate oral iron response.

Direct Comparison of the Safety and Efficacy of Ferric Carboxymaltose versus Iron Dextran in Patients with Iron Deficiency Anemia.

Several intravenous iron complexes are available for the treatment of iron deficiency anemia (IDA). Iron dextran (DEX) is associated with an elevated risk of potentially serious anaphylactic reactions, whereas others must be administered in several small infusions to avoid labile iron reactions. Ferric carboxymaltose (FCM) is a nondextran intravenous iron which can be administered in high single doses. A randomized, open label, and multicenter comparison of FCM to DEX in adults with IDA and baseline hemoglobin of ≤11.0 g/dL was conducted. A total of 160 patients were in the safety population (FCM n = 82; DEX n = 78). Adverse events, including immune system disorders (0% in FCM versus 10.3% in DEX, P = 0.003) and skin disorders (7.3% in FCM versus 24.4% in DEX, P = 0.004), were less frequently observed in the FCM group. A greater portion of patients in the FCM group experienced a transient, asymptomatic decrease in phosphate compared to patients in the DEX group (8.5% in FCM versus 0% in DEX, P = 0.014). In the FCM arm, the change in hemoglobin from baseline to the highest observed level was 2.8 g/dL, whereas the DEX arm displayed a change of 2.4 g/dL (P = 0.20). Treatment of IDA with FCM resulted in fewer hypersensitivity-related reactions than DEX.

Comparative review of the safety and efficacy of ferric carboxymaltose versus standard medical care for the treatment of iron deficiency anemia in bariatric and gastric surgery patients.

BACKGROUND: Iron deficiency anemia (IDA) is a common finding in patients after bariatric surgery. The cause is multifactorial including reduced oral iron intake and malabsorption. While many patients can be managed with oral supplements, parenteral iron may be needed to restore and maintain iron stores. METHODS: Subjects who had previous bariatric surgery and had participated in phase 3 industry-sponsored clinical trials designed to assess the safety and/or efficacy of intravenous (IV) ferric carboxymaltose (FCM) were retrospectively selected from the databases of each of these studies. Demographic data, efficacy measures [hemoglobin, ferritin, and transferrin saturation (TSAT)], and adverse events were compared between FCM and other agents utilized as comparators in the trials. RESULTS: Two hundred eighty-one subjects from the intention to treat (ITT) population were included (mean age 49 years, BMI 33 kg/m(2), including 253 females). FCM had similar or improved efficacy (p < 0.05) in terms of increasing hemoglobin, ferritin, and TSAT values when compared to other iron products used as standard of care for IDA. The incidence of adverse events in the FCM patients (n = 123) versus patients receiving any IV iron (n = 126) was 61 and 56.3 %, respectively. The adverse events were similar in both groups with the exception of a transient decrease in serum phosphate which was observed more frequently in the FCM group. CONCLUSIONS: These data in post-bariatric surgery IDA patients suggest that FCM is a safe and effective alternative to existing iron products permitting higher and thus less frequent individual doses.

Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women.

Fibroblast growth factor 23 (FGF23) is an osteocyte-derived hormone that regulates phosphate and vitamin D homeostasis. Through unknown mechanisms, certain intravenous iron preparations induce acute, reversible increases in circulating FGF23 levels that lower serum phosphate in association with inappropriately low levels of calcitriol, similar to genetic diseases of primary FGF23 excess. In contrast, studies in wild-type mice suggest that iron deficiency stimulates fgf23 transcription but does not result in hypophosphatemia because FGF23 is cleaved within osteocytes by an unknown catabolic system. We tested the association of iron deficiency anemia with C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 55 women with a history of heavy uterine bleeding, and assessed the longitudinal biochemical response over 35 days to equivalent doses of randomly-assigned, intravenous elemental iron in the form of ferric carboxymaltose (FCM) or iron dextran. Iron deficiency was associated with markedly elevated cFGF23 (807.8 ± 123.9 relative units [RU]/mL) but normal iFGF23 (28.5 ± 1.1 pg/mL) levels at baseline. Within 24 hours of iron administration, cFGF23 levels fell by approximately 80% in both groups. In contrast, iFGF23 transiently increased in the FCM group alone, and was followed by a transient, asymptomatic reduction in serum phosphate <2.0 mg/dL in 10 women in the FCM group compared to none in the iron dextran group. Reduced serum phosphate was accompanied by increased urinary fractional excretion of phosphate, decreased calcitriol levels, and increased parathyroid hormone levels. These findings suggest that iron deficiency increases cFGF23 levels, and that certain iron preparations temporarily increase iFGF23 levels. We propose that intravenous iron lowers cFGF23 in humans by reducing fgf23 transcription as it does in mice, whereas carbohydrate moieties in certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to transient increases in iFGF23 and reduced serum phosphate.

Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia.

Levels of hepcidin, a major regulator of iron homeostasis, may identify patients with iron deficiency anemia (IDA) who will not respond to oral iron therapy. In this study, IDA patients underwent a 14-day trial (run-in) course of ferrous sulfate therapy. Nonresponders (Hgb increase <1 g/dL with 67% compliance rate) were randomized to IV ferric carboxymaltose (FCM; two injections of 750 mg) or further oral iron for 14 days. Screening hepcidin levels were 38.4 versus 11.3 ng/mL, P = 0.0002 in nonresponders versus responders to a trial of oral iron. Hepcidin of > 20 ng/mL, showed sensitivity of 41.3%, specificity of 84.4%, and positive predictive value of 81.6% for predicting nonresponsiveness to oral iron. PPVs for ferritin> 30 ng/mL or transferrin saturation (TSAT)>15% were 59.2 and 55%, respectively. Negative predictive values for hepcidin, ferritin, and TSAT were 46.3, 22.7, and 19.7, respectively. FCM versus oral iron showed Hgb increases of ≥ 1 gm/dL in 65.3% versus 20.8% (P < 0.0001) and Hgb increases of 1.7 ± 1.3 versus 0.6 ± 0.9 g/dL (P = 0.0025), respectively. We conclude that hepcidin predicts nonresponsiveness to oral iron in patients with IDA and is superior to TSAT or ferritin for this purpose. Nonresponse to oral iron therapy does not rule out IDA, since two-thirds of patients subsequently responded to intravenous iron.

Intravenous ferric carboxymaltose versus standard medical care in the treatment of iron deficiency anemia in patients with chronic kidney disease: a randomized, active-controlled, multi-center study.

BACKGROUND: Currently available intravenous (IV) iron agents vary in indication, dosing regimens and safety profiles. Ferric carboxymaltose (FCM) is a stable, non-dextran-containing iron formulation developed for rapid IV administration in high doses with controlled delivery of iron into target tissues. The objective of the present study was to evaluate the safety of FCM compared with standard medical care (SMC) in dialysis (HD) and non-dialysis-dependent (NDD) chronic kidney disease (CKD) patients. METHODS: Adults 18-85 years of age with CKD were enrolled. NDD-CKD (n = 204) patients received an undiluted IV dose of FCM (15 mg/kg to a maximum of 1000 mg IV) and HD-CKD (n = 50) patients received an undiluted IV push of 200 mg ~30-60 min into the dialysis session. Subjects randomized to the SMC group (n = 259) received treatment determined by the investigator that could include oral iron, IV iron or no iron. RESULTS: Single doses of FCM of 200 mg in HD-CKD patients and up to 1000 mg in NDD-CKD patients were well tolerated. Incidences of treatment-emergent adverse events were similar between the groups: 30.3% (77 of 254) in the FCM group and 32.8% (85 of 259) in the SMC group. Incidences of serious adverse events were higher in the SMC group overall and in patients receiving iron sucrose or sodium ferric gluconate. There were no clinically significant differences in laboratory or clinical chemistry values or vital signs between the groups. There were no statistically significant differences between the FCM and SMC groups in indices of hemoglobin (Hb) improvement, including proportions of patients achieving a ≥ 1 g/dL increase in Hb and proportions of patients achieving Hb level of >12 g/dL. CONCLUSION: FCM in doses of 200 mg for HD-CKD patients and up to 1000 mg in NDD-CKD patients were well tolerated and displayed comparable efficacy to other IV iron formulations.

Safety and Efficacy of Intravenous Ferric Carboxymaltose (750 mg) in the Treatment of Iron Deficiency Anemia: Two Randomized, Controlled Trials.

Background. Iron deficiency anemia (IDA) is a common hematological complication with potentially serious clinical consequences that may require intravenous iron therapy. Ferric carboxymaltose (FCM) is a stable, nondextran iron formulation administered intravenously in large single doses to treat IDA. Objective. Two open-label, randomized, placebo-controlled trials evaluated safety of multiple or single 750 mg FCM doses compared to standard medical care (SMC) in IDA patients. Secondary endpoints were improvements in hemoglobin and iron indices. Design and Patients. Adults with hemoglobin ≤12 g/dL, ferritin ≤100 or ≤300 ng/mL with transferrin saturation ≤30% were randomized to receive single (n = 366) or weekly (n = 343) FCM or SMC (n = 360 and n = 366). Results. Significantly greater (P ≤ 0.001) increases in hemoglobin and iron indices occurred in FCM groups versus SMC. In the multidose study, up to two infusions of FCM were needed to reach target iron levels versus 3-5 of intravenous iron comparators. FCM and SMC groups had similar incidences and types of adverse events and serious adverse events. Transient hypophosphatemia not associated with adverse events or clinical sequelae occurred in the FCM groups. Conclusion. Intravenous FCM is safe, well tolerated, and associated with improvements in hemoglobin and iron indices comparable to SMC when administered in single doses of up to 750 mg at a rate of 100 mg/min. Fewer FCM infusions were required to reach target iron levels compared to other intravenous iron preparations.

Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial.

OBJECTIVE: Intravenous (IV) iron has been used as a treatment to reduce Restless Legs Syndrome (RLS) symptoms, but two double-blinded trials of a frequently prescribed IV iron formulation, iron sucrose, failed to show lasting efficacy. This study evaluates efficacy and safety of a new IV iron formulation (ferric carboxymaltose, FCM) with molecular properties that may make iron more available for uptake to the brain than iron sucrose does. METHODS: In this 28-day, multi-centre, randomised, placebo-controlled trial 46 RLS patients were discontinued from all RLS treatment. Twenty-four received 500 mg FCM in two doses 5 days apart and 22 received a matching placebo. At day 28, those on placebo were given a single 1000 mg IV FCM and those not responding to initial treatment were given a third dose of 500 mg FCM. Patients were followed up for 24 weeks or until needing added RLS treatment. RESULTS: FCM significantly improved primary and secondary outcomes compared to placebo: International Restless Legs Syndrome study group severity scale (IRLS) average (SD) decrease of 8.9 (8.52) versus 4.0 (6.11), p=0.040; Clinical Global Inventory of Change (CGI-1) very much or much improved 48.3% versus 14.3%, p=0.004. Quality of life was also significantly improved. Of the 24 with initial iron treatment 45% responded and 29% remitted (IRLS ≤ 10) at day 28, and 25% continued free of other RLS medications at 24 weeks after treatment. The single 1000 mg dose on day 28 produced the same degree of treatment response as the divided dose, but the added 500 mg dose for those not responding to the initial treatment showed little benefit. There were no significant adverse events. CONCLUSIONS: IV FCM provided a safe and effective treatment for RLS that lasted for at least 24 weeks for some patients. Larger studies are needed to confirm these results.

Randomized evaluation of efficacy and safety of ferric carboxymaltose in patients with iron deficiency anaemia and impaired renal function (REPAIR-IDA): rationale and study design.

BACKGROUND: Patients with iron deficiency anaemia (IDA) in the setting of non-dialysis-dependent chronic kidney disease (NDD-CKD) may benefit from treatment with intravenous (IV) iron. Ferric carboxymaltose (FCM) is a novel IV iron formulation designed to permit larger infusions compared to currently available IV standards such as Venofer(R) (iron sucrose). METHODS: The primary objective of REPAIR-IDA is to estimate the cardiovascular safety and efficacy of FCM (two doses at 15 mg/kg to a maximum of 750 mg per dose) compared to Venofer(R) (1000 mg administered as five infusions of 200 mg) in subjects who have IDA and NDD-CKD. REPAIR-IDA is a multi-centre, randomized, active-controlled, open-label study. Eligible patients must have haemoglobin (Hgb) < or = 11.5 g/dL and CKD defined as (1) GFR < 60 mL/min/1.73 m(2) on two occasions or (2) GFR < 90 mL/min/1.73 m(2) and either evidence of renal injury by urinalysis or elevated Framingham cardiovascular risk score. Two thousand and five hundred patients will be randomized to FCM or Venofer(R) in a 1:1 ratio. The primary efficacy endpoint is mean change in Hgb from baseline to the highest observed Hgb between baseline and Day 56. The primary safety endpoint is the proportion of subjects experiencing at least one of the following events: death due to any cause, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization or medical intervention, arrhythmias, hypertension or hypotension during the 120 days following randomization. CONCLUSION: REPAIR-IDA will assess the efficacy and safety of two 750-mg infusions of FCM compared to an FDA-approved IV iron regimen in patients with NDD-CKD at increased risk for cardiovascular disease.

Efficacy of cholesterol uptake inhibition added to statin therapy among subjects following a low-carbohydrate diet: a randomized controlled trial.

BACKGROUND: Low-carbohydrate diets are frequently used as part of weight-loss programs. These are typically associated with increased fat intake. Therefore, cholesterol absorption inhibition is a logical therapeutic strategy to lower low-density lipoprotein cholesterol (LDL-C) in subjects following a low-carbohydrate diet. However, the efficacy of cholesterol absorption inhibition added to statin therapy has not been studied in this common clinical setting. METHODS: We performed a randomized controlled trial to compare the effects of ezetimibe on LDL-C when added to simvastatin among subjects following a low-carbohydrate diet. We enrolled 65 subjects who were overweight or obese (body mass index 25-45 kg/m(2)) and had a moderately elevated LDL-C (130-190 mg/dL). During a 4-week diet run-in, subjects were instructed to restrict carbohydrate intake to <30 g/day. Subjects demonstrating adequate adherence to a low-carbohydrate diet (n = 58) were randomized to simvastatin (20 mg) or simvastatin (20 mg) plus ezetimibe (10 mg) for 8 weeks. RESULTS: Body weight decreased by 3.1% (95% CI 2.1%-4.0%, P < .0001), but the magnitude of weight change did not differ between the groups (P = .92). The LDL-C decreased by 32 mg/dL (95% CI 21-42 mg/dL) in the simvastatin arm and 60 mg/dL (95% CI 45-75 mg/dL) in the combined simvastatin-ezetimibe arm (P = .002). This corresponded to a 20.9% reduction (95% CI 14.5%-27.4%) in LDL-C on simvastatin alone, compared with a 37.4% reduction (95% CI 29.3%-45.6%) on simvastatin-ezetimibe (P = .002). A significant 15.8% reduction in triglycerides was observed among enrolled subjects, which did not differ between the groups. CONCLUSIONS: Among subjects following a low-carbohydrate diet, combined statin and cholesterol absorption inhibitor therapy is more effective than statin monotherapy for LDL-C lowering.

An internet-based simulation system for training and development of regional-healthcare-centers managers.

RHCMS (Regional Healthcare Center Management System) is an Internet-based simulation training system for Regional Healthcare-Centers (RHCs) managers. The system is based on an integrative model, designed and developed by an interdisciplinary team of experts, for the purpose of training and developing RHCs' managers. This model involves the study of the following fields: healthcare management, business administration, organizational behavior, health economics, management science, and information technologies. The simulation system enables the operation of a management decision-making game. In the game, teams of trainees, playing management teams of RHCs, within one specific community, compete among themselves. The simulation focuses on managerial performance, based on periodic team-decisions, within the internal and external environmental context. The simulation game has a major potential contribution in enabling management trainees to transfer theoretical knowledge into managerial practical tools, capabilities and skills.

The inhibitor of cyclin-dependent kinase 4a/alternative reading frame (INK4a/ARF) locus encoded proteins p16INK4a and p19ARF repress cyclin D1 transcription through distinct cis elements.

The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF) (murine p19(ARF)). Invariant inactivation of either the p16(INK4a)-cyclin D/CDK-pRb pathway and/or p53-p14(ARF) pathway occurs in most human tumors. Cyclin D1 is frequently overexpressed in breast cancer cells contributing an alternate mechanism inactivating the p16(INK4a)/pRb pathway. Targeted overexpression of cyclin D1 to the mammary gland is sufficient for tumorigenesis, and cyclin D1-/- mice are resistant to Ras-induced mammary tumors. Recent studies suggest cyclin D1 and p16(INK4a) expression are reciprocal in human breast cancers. Herein, reciprocal regulation of cyclin D1 and p16(INK4a) was observed in tissues of mice mutant for the Ink4a/Arf locus. p16(INK4a) and p19(ARF) inhibited DNA synthesis in MCF7 cells. p16(INK4a) repressed cyclin D1 expression and transcription. Repression of cyclin D1 by p16(INK4a) occurred independently of the p16(INK4a)-cdk4-binding function and required a cAMP-response element/activating transcription factor-2-binding site. p19(ARF) repressed cyclin D1 through a novel distal cis-element at -1137, which bound p53 in chromatin-immunoprecipitation assays. Transcriptional repression of the cyclin D1 gene through distinct DNA sequences may contribute to the tumor suppressor function of the Ink4a/Arf locus.

Simulation and management games for training command and control in emergencies.

The aim of our project was to introduce and implement simulation techniques in a problematic field of increasing health care system preparedness for disasters. This field was chosen as knowledge is gained by few experienced staff members who need to disperse it to others during the busy routine work of the system personnel. Knowledge management techniques ranging from classifying the current data, centralized organizational knowledge storage and using it for decision making and dispersing it through the organization--were used in this project. In the first stage we analyzed the current system of building a preparedness protocol (set of orders). We identified the pitfalls of changing personnel and loosing knowledge gained through lessons from local and national experience. For this stage we developed a database of resources and objects (casualties) to be used in the simulation in different possibilities. One of those was the differentiation between drills with trainer and those in front of computers enable to set the needed solution. The model rules for different scenarios of multi-casualty incidents from conventional warfare trauma to combined chemical/toxicological as well as, levels of care pre and inside hospitals--were incorporated to the database management system (we used Microsoft Access' DBMS). The hardware for management game was comprised of serial computers with network and possibility of projection of scenes. For prehospital phase the possibility of portable PC's and connections to central server was used to assess bidirectional flow of information. Simulation software (ARENA) and graphical interfase (Visual Basic, GUI) as shown in the attached figure. We hereby conclude that our system provides solutions which are in use in different levels of healthcare system to assess and improve management command and control for different scenarios of multi-casualty incidents.

National strategy for mass casualty situations and its effects on the hospital.

A mass-casualty situation (MCS) usually is short in duration and resolves itself. To minimize the risks to patients during MCS, planning is essential. This article summarizes the preparations needed at the hospital level, for a local MCS involving numerous trauma victims arriving to the Emergency Department at a short notice. Experiences and conclusions related to the implementation of the Israeli strategy in one hospital that combines the responsibilities of both the military and civilians are summarized. The Ministry of Health distributes the master MCS plan to each hospital where a local committee adapts it to the specific situation in a format of standing orders. After its approval by the Ministry of Health, an annual inspection is conducted to check the ability of the staff to manage a MCS. A full-scale drill is conducted every second year during which each site's readiness level and the continuity of the flow of care are tested. In building the strategy for treating trauma victims during a MCS, a few assumptions were taken into account. The goal of treatment in a MCS is to deliver an acceptable quality of care while preserving as many lives as is possible. In theory, the capacity of the hospital is its ability to manage a load of patients in the range of 20% of the hospital bed capacity. Planning and drilling are the ways to minimize deviations from the guidelines and to avoid management mistakes. Special attention should be paid to problems related to the initial phase of receiving the first message, outside communication, inside hospital communication, and staff recruitment. Other issues include: free access to the hospital; opening a public information center; and dealing with the media and very important persons (VIPs). A new method for creating the needed MCS plan in the hospital is suggested. It is based upon knowledge of management techniques that used multi-level documents, which are spread via Intranet between the different key figures. Using this method, it is possible to keep the strategy, the source documentation, and reasons for choosing it, as well as immediate release of checklists for each functions. This detailed, time consuming work is worthwhile in the long run, when the benefits of easy updating and better preparedness are apparent.

RNA polymerase II large subunit is cleaved by caspases during DNA damage-induced apoptosis.

UV radiation induces DNA lesions that are repaired by the nucleotide excision repair (NER) pathway. Cells that are NER deficient such as those derived from xeroderma pigmentosum (XP) patients are susceptible to apoptosis after 10J/m(2) UV radiation, a dose largely survivable by repair proficient cells. Herein, we report that RNA polymerase II large subunit (RNAP II-LS) undergoes caspase-mediated cleavage, yielding a 140kDa C-terminal fragment in XP lymphoblasts but not NER proficient lymphoblasts after 10J/m(2) UV irradiation. Cleavage could also be induced by cisplatin or oxaliplatin, but not transplatin, an isomer of cisplatin that does not induce DNA adducts. The cleavage of RNAP II-LS was blocked by a panel of caspase inhibitors but not by proteasomal inhibitors or inhibitors of other proteases. In vitro cleavage with caspase 8 yielded the same 140kDa RNAP II-LS fragment observed in vivo. Using site-directed mutagenesis, the RNAP II-LS cleavage site was localized to an LETD sequence ending at residue 1339, which is near its C-terminal domain.